PI: Khalil, Ahmad Technical Abstract: Colon cancer is the second leading cause of cancer-related death in the United States, largely due to frequent treatment failure and recurrence. Recent studies, including work from our laboratory, have demonstrated that regulatory long intergenic non-coding RNAs (lincRNAs) are major players in the process of colon tumorigenesis, and could emerge as novel therapeutic targets. In this proposal, we have identified and functionally characterized a novel lincRNA, referred to as lincDUSP, that exerts an oncogenic effect in colon cancer cells. Knockdown of lincDUSP significantly abrogates the tumor phenotype, including decreased proliferation and colony formation, and increased apoptosis. These studies have also revealed that lincDUSP regulates numerous genes by directly interacting with chromatin, and potentially recruiting protein complexes to specific genomic loci. In aim 1 of this proposal, we will further test the oncogenic function of lincDUSP in vivo using a xenograft model, and also assess the role of lincDUSP in driving colon tumorigenesis using 3D organoids. In aim 2, we will investigate the molecular mechanisms of lincDUSP by assessing its role in gene regulation, and characterize the protein complexes that are required for lincDUSP oncogenic activity. Lastly, we will determine the secondary structure of lincDUSP that facilitates its interaction with DNA and proteins. The completion of the proposed studies could lead to establishing lincDUSP as a novel oncogenic lincRNA with direct impact on colon tumorigenesis, and possibly as a target for therapy.